Oral sustained-release preparation of fasudil hydrochloride

ABSTRACT

Disclosed is an oral sustained-release preparation which contains at least one active-ingredient selected from the group consisting of fasudil hydrochloride and a hydrate thereof, the preparation comprising at least one sustained-release coated particle comprising a core having a surface and a coating formed on the surface of the core, wherein the core contains the active ingredient and the coating comprises a coating base material and a specific insoluble auxiliary material, and wherein the preparation exhibits, with respect to the active ingredient, a specific dissolution rate, as measured by the dissolution test. By using the oral sustained-release preparation of the present invention, it becomes possible to surely control the release of fasudil hydrochloride from the preparation, so that the effect of the active ingredient is maintained for a long period of time. Therefore, the burden of the patient who has to take the preparation can be decreased and the compliance with respect to the administration of the preparation can be improved. Also disclosed is a method for evaluating an oral sustained-release preparation containing the active ingredient, wherein the evaluation is conducted with respect to the sustained-release ability of the active ingredient.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention-relates to an oral sustained-release preparation.More particularly, the present invention is concerned with an oralsustained-release preparation which contains at least one activeingredient selected from the group consisting of fasudil hydrochlorideand a hydrate thereof, the preparation comprising at least onesustained-release coated particle comprising a core having a surface anda coating formed on the surface of the core, wherein the core containsthe active ingredient and the coating comprises a coating base materialand a specific insoluble auxiliary material, the preparation exhibitinga specific dissolution rate with respect to the active ingredient, asmeasured by the dissolution test. The present invention is alsoconcerned with a method for evaluating an oral sustained-releasepreparation containing the active ingredient, the evaluation beingconducted with respect to the sustained-release ability of the activeingredient.

By using the oral sustained-release preparation of the presentinvention, it becomes possible to surely control the release of fasudilhydrochloride from the preparation, so that a desired amount of fasudilhydrochloride is continued to be released from the preparation for along period of time, and that the effect of fasudil hydrochloride ismaintained for a relatively long period of time. Therefore, thefrequency of the administration of the preparation becomes low, so thatthe burden of the patient who has to take the preparation can bedecreased and the compliance with respect to the administration of thepreparation can be improved. As a result, the therapeutic effect offasudil hydrochloride is rendered reliable. Therefore, the oralsustained-release preparation of the present invention is extremelyuseful.

2. Prior Art

1-(5-Isoquinolinesulfonyl)homopiperazine hydrochloride (hereinbelowreferred to as “fasudil hydrochloride”) has excellent vasodilativeactivity and is clinically used for treating cerebral vasospasm (whichis likely to occur after the operation of a patient suffering fromsubarachnoid hemorrhage), cerebral ischemic symptoms accompanying thecerebral vasospasm, and the like, wherein the above-mentioned fasudilhydrochloride is used in the form of a parenteral preparation which isavailable under tradename “Eril Inj.” (registered trademark for theproduct produced and sold by Asahi Kasei Kogyo Kabushiki Kaisha, Japan)(see Unexamined Japanese Patent Application Laid-Open Specification No.5-3851 (corresponding to U.S. Pat. No. 4,678,783)).

There are two conventionally known different types of crystals offasudil hydrochloride, i.e., crystals containing no water ofcrystallization (hereinbelow referred to as “fasudil hydrochlorideanhydride”) and crystals containing water of crystallization(hereinbelow referred to as “fasudil hydrochloride hydrate”) (seeInternational Patent Application Publication No. WO97/02260(corresponding to EP 0 870 767 A1)).

SUMMARY OF THE INVENTION

Fasudil hydrochloride has excellent vasodilative activity. For thisreason, it is expected that fasudil hydrochloride is provided in theform of various types of preparations, wherein the administration route,manner of administration, dosage and the like of the preparations aredifferent from those of the above-mentioned parenteral preparation.

For example, due to the excellent vasodilative activity, fasudilhydrochloride can be used as a drug for treating an ischemic disease(especially, angina pectoris). With respect to a preparation containingfasudil hydrochloride as an active ingredient, which is used as a drugfor treating an ischemic disease, an oral preparation can be taken bythe patient himself at his home, whereas a parenteral preparation mustbe administered by a doctor at a hospital. Therefore, the oralpreparation can extremely decrease the burden of the patient sufferingfrom an ischemic disease, which needs his attendance at a hospital forthe treatment of the disease.

From the above-mentioned viewpoint, the present inventors attempteddeveloping an oral preparation containing fasudil hydrochloride as anactive ingredient, which is used as a drug for treating an ischemicdisease (such as angina pectoris).

In the course of the development of the oral preparation, it has beenfound that the conventional oral preparation (containing fasudilhydrochloride as an active ingredient) is required to be administered asfrequently as 3 times a day for achieving a satisfactory therapeuticeffect. However, with respect to a disease (such as an ischemic disease)which should be treated by administering a drug for a long period oftime, when a preparation used as a drug for treating the disease shouldbe frequently administered, in many cases, the so-called “compliance”with respect to the administration of the preparation is low. This lowcompliance is caused by the fact that when the preparation should befrequently administered, in many cases, the patient forgets to take thepreparation. As a result, the therapeutic effect of the preparationcannot be surely achieved.

For this reason, in order to surely achieve the therapeutic effect ofthe preparation, it is considered preferable that the frequency of theadministration of the preparation is lowered so that the compliance isimproved and the burden of the patient who has to take the preparationis decreased.

As an example of the method effective for lowering the frequency of theadministration of the preparation, there can be mentioned a method inwhich the preparation is prepared in a sustained-release form.Therefore, the present inventors attempted developing asustained-release preparation containing fasudil hydrochloride as anactive ingredient. As a result, it has been found that in order todevelop such a preparation, the below-mentioned two problems should besolved.

One of the two problems is how to realize a controlled dissolution offasudil hydrochloride.

Generally, when the dissolution rate of the drug from the preparation isappropriately controlled, the drug is gradually released from thepreparation (which contains a relatively large amount of the drug) overa relatively long period of time (hereinafter referred to simply as“over a long period of time”). When such a preparation(sustained-release preparation) is administered to a patient, a desiredamount of the drug is gradually released from the preparation over along period of time. As a result, the concentration of the drug in theblood of the patient is kept in a desired range, so that the effect ofthe drug is maintained for a long period of time. Further, by virtue ofthe effect maintained for a long period of time, the frequency of theadministration of the preparation can be lowered.

There are many reports on the techniques for producing asustained-release preparation. These techniques have been applied tomany drugs, and various kinds of useful sustained-release preparationshave been developed.

However, it is extremely difficult to control, by conventional methods,the release of fasudil hydrochloride from the preparation containingfasudil hydrochloride. In fact, the present inventors tried to develop asustained-release preparation containing fasudil hydrochloride as anactive ingredient using various techniques reported up to the present,but fasudil hydrochloride was rapidly released from the preparation, andit was not possible to control the release of fasudil hydrochloride.This problem is essentially caused by the fact that fasudilhydrochloride is extremely soluble in water.

In addition, in order to maintain the effect of fasudil hydrochloridefor a long period of time, the concentration of the active metabolite offasudil hydrochloride (mentioned below) in blood should be kept in adesired range for a long period of time. In order to achieve this, it isrequired to use a preparation in which even in the upper portion of thedigestive tract (in which the amount of the internal-liquid of thedigestive tract is large), fasudil hydrochloride is not rapidly releasedfrom the preparation, and in which even in the lower portion of thedigestive tract (in which the amount of the internal liquid in thedigestive tract is small), the amount of fasudil hydrochloride releasedfrom the preparation is satisfactory.

For this reason, a sustained-release preparation containing fasudilhydrochloride as an active ingredient should exhibit the following twocontradictory functions:

-   i) surely preventing rapid release of fasudil hydrochloride, even in    the presence of a large amount of water, and-   ii) surely releasing fasudil hydrochloride in a satisfactory amount    for a long period of time, even in the presence of a small amount of    water.

By a conventional method, it was extremely difficult to develop such apreparation.

The remainder of the two problems is how to control the kinetics offasudil hydrochloride in a living body.

Most of fasudil hydrochloride (which is orally administered to a human)is metabolized and transferred to circulating blood. Only a small amountof fasudil hydrochloride is transferred to circulating blood withoutbeing metabolized. The main metabolite generated from fasudilhydrochloride is 1-hydroxy derivative (in which a hydroxyl group isintroduced into the 1-position of the isoquinoline skeleton of fasudilhydrochloride), and this 1-hydroxy derivative exhibits pharmaceuticalactivities in a living body. In other words, actually, thepharmaceutical activities of fasudil hydrochloride are exhibited by this1-hydroxy derivative (hereinafter, this 1-hydroxy derivative, which isan active metabolite derived from fasudil hydrochloride, is referred tosimply as the “active metabolite”). Therefore, in order to maintain thepharmaceutical activities of fasudil hydrochloride for a long period oftime, the concentration of this active metabolite (not fasudilhydrochloride as such) in the blood should be kept in a desired rangefor a long period of time.

However, the active metabolite is rapidly eliminated from blood.Therefore, in order to keep the concentration of the active metabolitein the blood in a desired range for a long period of time, the activemetabolite should be continued to be transferred to circulating blood.In order to achieve this, it is considered to be required that, duringthe transfer of the preparation containing fasudil hydrochloride as anactive ingredient (which is orally administered) to the lower portion ofthe digestive tract through the entrance into the digestive tract, adesired amount of fasudil hydrochloride is continued to be released fromthe preparation, absorbed over the whole region of the digestive tractand metabolized to the active metabolite, and, in turn, the activemetabolite is continued to be transferred to circulating blood.

However, it is conventionally known that with respect to many drugs, theabsorption rate, metabolism rate and the like vary depending on theportion in the digestive tract in which the absorption, metabolism andthe like of the drug occur. In some cases, the mode in which the drug ismetabolized varies depending on the portion in the digestive tract inwhich the metabolism of the drug occurs. For this reason, the design fora sustained-release preparation (especially an oral sustained-releasepreparation) containing a drug which exhibits pharmaceutical activitiesafter being metabolized (such as fasudil hydrochloride) is extremelydifficult. In other words, for keeping the concentration of the activemetabolite in blood in a desired range for a long period of time, it isextremely difficult to select the releasing pattern of fasudilhydrochloride from the preparation.

In this situation, the present inventors have made extensive andintensive studies with a view toward solving the above-mentioned twoproblems and developing an oral sustained-release preparation containingfasudil hydrochloride as an active ingredient, which releases a desiredamount of fasudil hydrochloride for a long period of time and is capableof maintaining the effects of fasudil hydrochloride for a long period oftime. As a result, it has been unexpectedly found that when the oralsustained-release preparation (containing fasudil hydrochloride as anactive ingredient) is a preparation comprising at least onesustained-release coated particle comprising a core having a surface anda coating formed on the surface of the core, wherein the core containsthe active ingredient and the coating comprises a coating base materialand a specific insoluble auxiliary material, it becomes possible tosurely control the release of fasudil hydrochloride from thepreparation, and that the amount of water present around theabove-mentioned preparation has almost no influence on the release offasudil hydrochloride from the preparation.

Further, it has also been unexpectedly found that when the preparationcontaining fasudil hydrochloride as an active ingredient exhibits aspecific dissolution rate with respect to the active ingredient, asmeasured by the dissolution test, it becomes possible to keep theconcentration of the active metabolite in blood in a desired range for along period of time.

The present invention has been completed, based on these novel findings.

Accordingly, it is a primary object of the present invention to providean oral sustained-release preparation containing fasudil hydrochlorideas an active ingredient, which releases a desired amount of fasudilhydrochloride for a long period of time and is capable of maintainingthe effects of fasudil hydrochloride (exactly, the effects of 1-hydroxyderivative of fasudil hydrochloride) for a long period of time.

It is another object of the present invention to provide a method forevaluating an oral sustained-release preparation which contains fasudilhydrochloride as an active ingredient, the evaluation being conductedwith respect to the sustained-release ability of the preparation withrespect to the fasudil hydrochloride contained therein.

The foregoing and other objects, features and advantages of the presentinvention will be apparent from the following detailed description takenin connection with the accompanying drawings and the appended claims.

BRIEF DESCRIPTION OF THE DRAWING

In the accompanying drawings:

FIG. 1 is a graph showing the change (with the lapse of time) of theplasma concentration of the active metabolite (1-hydroxy derivative offasudil hydrochloride) in rats, which is obtained by orallyadministering the oral sustained-release preparation produced in Example2.

FIG. 2 is a graph showing the change (with the lapse of time) of theplasma concentration of the active metabolite in rats, which is obtainedby orally administering the oral sustained-release preparation producedin Example 3.

FIG. 3 is a graph showing the change (with the lapse of time) of theplasma concentration of the active metabolite in rats, which is obtainedby orally administering the oral sustained-release preparation producedin Example 4.

FIG. 4 is a graph showing the change (with the lapse of time) of theplasma concentration of the active metabolite in rats, which is obtainedby orally administering the oral sustained-release preparation producedin Example 8.

FIG. 5 is a graph showing the change (with the lapse of time) of theplasma concentration of the active metabolite in rats, which is obtainedby orally administering the oral sustained-release preparation producedin Example 10.

FIG. 6 is a graph showing the change (with the lapse of time) of theplasma concentration of the active metabolite in rats, which is obtainedby orally administering the oral sustained-release preparation producedin Comparative Example 3.

FIG. 7 is a graph showing the change (with the lapse of time) of theplasma concentration of the active metabolite in rats, which is obtainedby orally administering the oral sustained-release preparation producedin Comparative Example 4.

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention, there is provided an oralsustained-release preparation which contains at least one activeingredient selected from the group consisting of fasudil hydrochlorideand a hydrate thereof, wherein the fasudil hydrochloride is representedby the following formula:

the preparation comprising at least one sustained-release coatedparticle comprising a core having a surface and a coating formed on thesurface of the core, wherein the core contains the active ingredient andthe coating comprises a coating base material and an insoluble auxiliarymaterial which is pharmaceutically acceptable and insoluble in water andethanol,

the preparation exhibiting, with respect to the active ingredient, thefollowing dissolution rates (1), (2) and (3), as measured by method-2(paddle method) of the dissolution test described in the JapanesePharmacopoeia Thirteenth Edition:

(1) dissolution of 5 to 40% by weight, based on the weight of the activeingredient originally contained in the preparation, at the point in timeof 3 hours after the start of the dissolution test,

(2) dissolution of 35 to 70% by weight, based on the weight of theactive ingredient originally contained in the preparation, at the pointin time of 6 hours after the start of the dissolution test, and

(3) dissolution of 70% by weight or more, based on the weight of theactive ingredient originally contained in the preparation, at the pointin time of 15 hours after the start of the dissolution test.

For easy understanding of the present invention, the essential featuresand various preferred embodiments of the present invention areenumerated below.

-   1. An oral sustained-release preparation which contains at least one    active ingredient selected from the group consisting of fasudil    hydrochloride and a hydrate thereof, wherein the fasudil    hydrochloride is represented by the following formula:

the preparation comprising at least one sustained-release coatedparticle comprising a core having a surface and a coating formed on thesurface of the core, wherein the core contains the active ingredient andthe coating comprises a coating base material and an insoluble auxiliarymaterial which is pharmaceutically acceptable and insoluble in water andethanol, the preparation exhibiting, with respect to the activeingredient, the following dissolution rates (1), (2) and (3), asmeasured by method 2 (paddle method) of the dissolution test describedin the Japanese Pharmacopoeia Thirteenth Edition:

(1) dissolution of 5 to 40% by weight, based on the weight of the activeingredient originally contained in the preparation, at the point in timeof 3 hours after the start of the dissolution test,

(2) dissolution of 35 to 70% by weight, based on the weight of theactive ingredient originally contained in the preparation, at the pointin time of 6 hours after the start of the dissolution test, and

(3) dissolution of 70% by weight or more, based on the weight of theactive ingredient originally contained in the preparation, at the pointin time of 15 hours after the start of the dissolution test.

-   2. The oral sustained-release preparation according to item 1 above,    wherein the amount of the active ingredient which is contained in    the core is at least 30% by weight, based on the weight of the    active ingredient contained in the preparation.-   3. The oral sustained-release preparation according to item 1 above,    wherein the amount of the active ingredient which is contained in    the core is substantially 100% by weight, based on the weight of the    active ingredient contained in the preparation.-   4. The oral sustained-release preparation according to any one of    items 1 to 3 above, wherein the coating contains 0.5 to 10 parts by    weight of the insoluble auxiliary material, per part by weight of    the coating base material.-   5. The oral sustained-release preparation according to any one of    items 1 to 4 above, wherein the insoluble auxiliary material is at    least one member selected from the group consisting of magnesium    stearate, calcium stearate, talc, titanium oxide and light anhydrous    silicic acid.-   6. The oral sustained-release preparation according to any one of    items 1 to 5 above, wherein the coating base material is    ethylcellulose and the insoluble auxiliary material is talc.-   7. The oral sustained-release preparation according to any one of    items 1 to 5 above, wherein the coating base material is    ethylcellulose and the insoluble auxiliary material is magnesium    stearate.-   8. The oral sustained-release preparation according to any one of    items 1 to 5 above, wherein the coating base material is a copolymer    of ethyl acrylate/methyl methacrylate/trimethylammonioethyl    methacrylate chloride and the insoluble auxiliary material is talc.-   9. An oral sustained-release preparation which contains at least one    active ingredient selected from the group consisting of fasudil    hydrochloride and a hydrate thereof, wherein the fasudil    hydrochloride is represented by the following formula:

the preparation exhibiting, with respect to the active ingradient, thefollowing dissolution rates (1), (2) and (3), as measured by method 2(paddle method) of the dissolution test described in the JapanesePharmacopoeia Thirteenth Edition:

(1) dissolution of 5 to 40% by weight, based on the weight of the activeingredient originally contained in the preparation, at the point in timeof 3 hours after the start of the dissolution test,

(2) dissolution of 35 to 70% by weight, based on the weight of theactive ingredient originally contained in the preparation, at the pointin time of 6 hours after the start of the dissolution test, and

(3) dissolution of 70% by weight or more, based on the weight of theactive ingredient originally contained in the preparation, at the pointin time of 15 hours after the start of the dissolution test.

-   10. A method for evaluating an oral sustained-release preparation    containing at least one active ingredient selected from the group    consisting of fasudil hydrochloride and a hydrate thereof, wherein    the fasudil hydrochloride is represented by the following formula:

the evaluation being conducted with respect to the sustained-releaseability of the preparation with respect to the fasudil hydrochloridecontained therein,

the method comprising subjecting the preparation to a testing accordingto a dissolution test method, the testing providing substantiallythe-same evaluation as the evaluation obtained by conducting a standardtesting according to method 2 (paddle method) of the dissolution testdescribed in the Japanese Pharmacopoeia Thirteenth Edition and assessinga dissolution of the active ingredient from the preparation by taking asa criterion the following dissolution rates (1), (2) and (3):

(1) dissolution of 5 to 40% by weight, based on the weight of the activeingredient originally contained in the preparation, at the point in timeof 3 hours after the start of the dissolution test,

(2) dissolution of 35 to 70% by weight, based on the weight of theactive ingredient originally contained in the preparation, at the pointin time of 6 hours after the start of the dissolution test, and

(3) dissolution of 70% by weight or more, based on the weight of theactive ingredient originally contained in the preparation, at the pointin time of 15 hours after the start of the dissolution test.

Hereinbelow, the present invention is described in detail.

The oral sustained-release preparation of the present invention containsat least one active ingredient selected from the group consisting offasudil hydrochloride and a hydrate thereof, wherein the fasudilhydrochloride is represented by the following formula:

Fasudil hydrochloride (anhydride) can be produced by a conventionalmethod, for example, the method described in Examined Japanese PatentApplication Publication No. 5-3851 (corresponding to U.S. Pat. No.4,678,783).

Further, a fasudil hydrochloride hydrate can be produced by aconventional method, for example, the method described in InternationalPatent Application Publication No. WO 97/02260 (corresponding to EP 0870 767 A1). As fasudil hydrochloride hydrates, there are known, forexample, fasudil hydrochloride hemihydrate and fasudil hydrochloridetrihydrate. In the present invention, any of the known fasudilhydrochloride hydrates can be employed.

In the oral sustained-release preparation of the present invention, itis preferred that the active ingredient is selected from the groupconsisting of fasudil hydrochloride anhydride and fasudil hydrochloridehemihydrate.

In the present invention, when it is necessary to convert the weight ofa fasudil hydrochloride hydrate to the weight of fasudil hydrochlorideanhydride or vice versa, the conversion of the weight can be easilyachieved, using the molecular weight ratio between the anhydride and thehydrate (wherein the molecular weight of the water of hydration is alsotaken into consideration). For example, by multiplying the weight offasudil hydrochloride hemihydrate by 0.9733, the weight can be convertedinto the weight of fasudil hydrochloride anhydride.

The oral sustained-release preparation of the present inventioncomprises at least one sustained-release coated particle comprising acore having a surface and a coating formed on the surface of the core.

The above-mentioned term “particle” is used as a general term coveringvarious particles of various sizes, such as granules, powder and pills.In the present invention, it is preferred that the sustained-releasecoated particle is a granule.

The oral sustained-release preparation of the present invention maycomprise only one sustained-release coated particle. However, it ispreferred that the oral sustained-release preparation of the presentinvention comprises several sustained-release coated particles.

The above-mentioned core contains the above-mentioned active ingredient.Specifically, the above-mentioned core contains at least a part of theabove-mentioned active ingredient. When the oral sustained-releasepreparation comprises a plurality of sustained-release coated particleseach containing the core, the plurality of cores collectively contain atleast a part of the above-mentioned active ingredient.

With respect to the weight ratio of the active ingredient which iscontained in the core to the entire active ingredient contained in theoral sustained-release preparation of the present invention, there is noparticular limitation. However, from the viewpoint of rendering uniformthe quality of the oral sustained-release preparation and preventing theoccurrence of a variation in amount of the active ingredient releasedfrom the preparation and absorbed by the body, it is preferred that theabove-mentioned weight ratio is as large as possible. In the presentinvention, it is preferred that the weight ratio of the activeingredient which is contained in the core is at least 30% by weight,more advantageously at least 60% by weight, still more advantageously atleast 80% by weight, most advantageously substantially 100% by weight,based on the weight of the active ingredient contained in the oralsustained-release preparation. The above-mentioned term “substantially100% by weight” means ordinarily 95% by weight or more, preferably 100%by weight.

With respect to the content of the active ingredient in the core, thereis no particularly limitation. However, it is preferred that the contentof the active ingredient in the core is 30% by weight or more., moreadvantageously 50% by weight or more, based on the weight of the core.The core may consist only of the active ingredient.

The amount of the active ingredient is defined as the weight of fasudilhydrochloride anhydride. That is, when a fasudil hydrochloride hydrateis used as the active ingredient, the weight of an equimolar amount offasudil hydrochloride anhydride is taken as the amount of the activeingredient.

With respect to the size of the core, there is no particularlylimitation. However, it is preferred that the core has an averageparticle diameter which is 100 pm or more, more advantageously 300 μm ormore, especially advantageously 500 μm or more. It is also preferredthat the average particle diameter of the core is 5,000 μm or less, moreadvantageously 2,000 μm or less, still more advantageously 1,500 μm orless, especially advantageously 1,000 μm or less.

The coating formed on the surface of the core comprises a coating basematerial and an insoluble auxciliary material which is pharmaceuticallyacceptable and insoluble in water and ethanol.

With respect to the coating base material used in the present invention,there is no particularly limitation as long as it is pharmaceuticallyacceptable and capable of forming a coating. Examples of coating basematerials include hydrophobic polymers and hydrophilic polymers. Thesepolymers can be used individually or in combination.

In the case of the coating base material composed of a hydrophobicpolymer, after the oral sustained-release preparation of the presentinvention has been administered, the internal liquid of the digestivetract permeates into and through the coating of the sustained-releasecoated particle, so that the liquid contacts the core in the particle.It is presumed that, as a result, the active ingredient in the core isdissolved in the liquid and the resultant solution permeates through thecoating, so that the active ingredient is released from thesustained-release coated particle.

In the case of the coating base material composed of a hydrophilicpolymer, after the oral sustained-release preparation of the presentinvention has been administered, the internal liquid of the digestivetract contacts and gradually dissolves or decomposes the coating of thesustained-release coated particle, so that a part of the surface of thecore in the particle is caused to contact the liquid. It is presumedthat, as a result, the active ingredient in the core is dissolved in theliquid and-released from the sustained-release coated particle.

Examples of hydrophobic polymers include cellulose ethers, such asethylcellulose and butylcellulose, cellulose esters, such as celluloseacetate and cellulose propionate, polyvinyl esters, such as polyvinylacetate and polyvinyl butyrate, and synthetic acrylic polymers, such asa copolymer of ethyl acrylate/methyl methacrylate/trimethylammonioethylmethacrylate chloride. These hydrophobic polymers can be usedindividually or in combination. Among these hydrophobic polymers,preferred are ethylcellulose, cellulose acetate and a copolymer of ethylacrylate/methyl methacryate/trimethylammonioethyl methacrylate chloride.

Hydrophilic polymers can be selected from water-soluble polymers,polymers soluble in intestine (enteric polymers), polymers soluble instomach (stomach-soluble polymers) and polymers soluble in both stomachand intestine (stomach/intestine-soluble polymers).

Examples of water-soluble polymers include pullulan, dextrin,hydroxypropylcellulose, hydroxypropylmethylcellulose,carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinylalcohol and polyethylene glycol. These water-soluble polymers can beused individually or in combination. Among these water-soluble polymers,preferred are hydroxypropylcellulose and hydroxypropylmethylcellulose.

The above-mentioned “enteric polymers” are polymeric substances whichare insoluble or stable under acidic conditions exhibiting a pH of lessthan 5 and which are dissolved or decomposed under conditions exhibitinga pH of 5 or more. Examples of such enteric polymers includecarboxymethylethylcelluldse, cellulose acetate phthalate, celluloseacetate succinate, methylcellulose phthalate,hydroxymethylethylcellulose phthalate, hydroxypropylmethylcellulosephthalate, hydroxypropylmethyl cellulose acetate succinate, polyvinylalcohol phthalate, polyvinyl butyrate phthalate, polyvinyl acetalphthalate, a copolymer of vinyl acetate/maleic anhydride, a copolymer ofvinylbutylether/maleic anhydride, a copolymer of styrene/maleic acidmonoester, a copolymer of methyl acrylate/methacrylic acid, a copolymerof styrene/acrylic acid, a copolymer of methyl acrylate/methacrylicacid/octyl acrylate and a copolymer of methacrylic acid/methylmethacrylate. These enteric polymers can be used individually or incombination. Among these enteric polymers, preferred arecarboxymethylethylcellulose, hydroxypropylmethylcellulose acetatesuccinate and a copolymer of methacrylic acid/methyl methacrylate.

The above-mentioned “stomach-soluble polymers” are polymeric substanceswhich are insoluble or stable under weakly acidic or basic conditionsexhibiting a pH of more than 6 and which are dissolved or decomposedunder conditions exhibiting a pH of 6 or less. Examples of suchstomach-soluble polymers include benzylaminomethylcellulose,diethylaminomethylcellulose, piperidylethylhydroxyethylcellulose,cellulose acetate dimethylaminoacetate, a copolymer of vinyldiethylamine/vinyl acetate, a copolymer of vinyl benzylamine/vinylacetate, polyvinyl acetal diethylamino acetate, a copolymer ofvinylpiperidyl acetoacetal/vinyl acetate, polydiethylaminomethylstyrene,a copolymer of methyl methacrylate/butyl methacrylate/dimethylaminoethylmethacrylate and polydimethylaminoethyl methacrylate. Thesestomach-soluble polymers can be used individually or in combination.Among these stomach-soluble polymers, preferred are polyvinyl acetaldiethylaminoacetate and a copolymer of methyl methacrylate/butylmethacrylate/dimethylaminoethyl methacrylate.

The above-mentioned “stomach/intestine-soluble polymers” are polymericsubstances which are insoluble or stable under conditions exhibiting apH of from more than 4.5 to less than 6 and which are dissolved ordecomposed under conditions exhibiting a pH of 4.5 or less or a pH of 6or more. Examples of such stomach/intestine-soluble polymers include acopolymer of 2-methyl-5-vinylpyridine/methyl methacrylate/methacrylicacid, a copolymer of 2-methyl-5-vinylpyridine /methylacrylate/methacrylic acid, a copolymer of2-vinyl-5-ethylpyridine/methacrylic acid/styrene, a copolymer of2-vinyl-5-ethylpyridine/methacrylic acid/methyl acrylate, a copolymer of2-vinylpyridine imethacrylic acid/methyl acrylate, a copolymer of2-vinylpyridine/methacrylic acid/acrylonitrile, carboxymethylpiperidylstarch, carboxymethylbenzylaminocellulose, poly(2-vinylphenylglycine)and a copolymer of N-vinylglycine/styrene. Thesestomach/intestine-soluble polymers can be used individually or incombination.

As mentioned above, the insoluble auxiliary material used in the presentinvention is a material which is pharmaceutically acceptable andinsoluble in water and ethanol. Herein, the term “insoluble” is intendedto mean being “practically insoluble” in the meaning as defined in item23 of the General Notices of the Japanese Pharmacopoeia ThirteenthEdition. That is, the term “insoluble” is intended to mean thatdissolution of 1 g or 1 ml of a certain substance in a certain solventneeds 10,000 ml or more of the solvent under given conditions.

Examples of insoluble auxiliary materials include talc, titanium oxide,magnesium stearate, calcium stearate and light anhydrous silicic acid.Of these, talc and magnesium stearate are preferred.

With respect to the amount of the insoluble auxiliary material, there isno particular limitation. However, it is preferred that the lower limitof the amount of the insoluble auxiliary material is 0.5 part by weight,more advantageously 0.7 part by weight, still more advantageously 1 partby weight, per part by weight of the coating base material. On the otherhand, it is preferred that the upper limit of the amount of theinsoluble auxiliary material is 10 parts by weight, more advantageously7 parts by weight, still more advantageously 5 parts by weight, per partby weight of the coating base material.

It is preferred that the insoluble auxiliary material is in the form ofa fine powder or fine particles. When the insoluble auxiliary materialis in the form of a fine powder or fine particles, it is preferred thatthe lower limit of the average particle diameter of the insolubleauxiliary material is 0.1 μm, more advantageously 0.3 μm, still moreadvantageously 0.5 μm. On the other hand, it is also preferred that theupper limit of the average particle diameter of the insoluble auxiliarymaterial is 300 μm, more advantageously 100 pm, still moreadvantageously 50 μm.

With respect to the combination of the types of the coating basematerial and the insoluble auxiliary material, there is no particularlimitation. However, preferred are the following combinations: acombination wherein the coating base material is ethylcellulose and theinsoluble auxiliary material is talc, a combination wherein the coatingbase material is ethylcellulose and the insoluble auxiliary material ismagnesium stearate, and a combination wherein the coating base materialis a copolymer of ethyl acrylate/methylmethacrylate/trimethylammonioethyl methacrylate chloride and theinsoluble auxiliary material is talc.

Further, it is preferred that the above-mentioned coating is uniformlyformed on the surface of the core. The thickness of the above-mentionedcoating is not particularly limited, but is preferably in the range offrom 5 to 100 μm, more preferably from 10 to 50 μm.

In the present invention, there is no particular limitation with respectto the method for producing the sustained-release coated particle.However, as an example of method for producing the sustained-releasecoated particle, there can be mentioned a method comprising preparing acore member containing at least one active ingredient selected from thegroup consisting of fasudil hydrochloride and a hydrate thereof, andforming, on the surface of the obtained core member, a coatingcomprising the above-mentioned coating base material and theabove-mentioned insoluble auxiliary material. With respect to thismethod for producing the sustained-release coated particle, a morespecific explanation is made below.

With respect to the shape of the core member, there is no particularlimitation. However, it is preferred that the core member has aspherical shape. There is also no particular limitation with resect tothe size of the core member. However, with respect to the averageparticle diameter of the core member, the lower limit is preferably 100μm, more preferably 300 μm, especially preferably 500 μm, and the upperlimit is preferably 5,000 μm, more preferably 2,000 μm, still morepreferably 1,500 μm, especially preferably 1,000 μm.

There is no particular limitation with respect to the method forproducing the core member. However, as examples of methods for producingthe core member, there can be mentioned the following methods:

(a) a method in which, using a centrifugal rolling granulator, a rollingfluid-bed granulator, a fluid-bed granulator or the like, the surface ofthe below-described nucleating excipient is applied with a fasudilhydrochloride-containing solution or suspension, while evaporating thesolvent contained in the solution or suspension applied to the surfaceof the nucleating excipient by heated air to thereby form a fasudilhydrochloride coating on the surface of the nucleating excipient andeffect granulation, followed by drying to obtain a core member;

(b) a method in which, using the above-mentioned granulator, the surfaceof the below-described nucleating excipient is applied with a powderyfasudil hydrchloride to thereby form a fasudil hydrochloride coating onthe surface of the nucleating excipient and effect granulation, followedby drying to obtain a core member; and

(c) a method in which, using a fluid-bed granulator, an extrusiongranulator or the like, a powdery fasudil hydrochloride is granulated bythe direct granulation method without using a nucleating excipient andthen, if desired, the resultant granule is rendered spherical using aspheronizer, thereby obtaining a core member.

The above-mentioned nucleating excipient functions as a nucleus forforming a granule by coating the surface of it with a drug. Thenucleating excipient is in a particulate form and is obtained bygranulating a pharmaceutically acceptable excipient. As an example ofcommercially available nucleating excipients, there can be mentioned anucleating excipient comprising sucrose, starch, a crystallinecellulose, or a mixture thereof.

Further, the production of the above-mentioned core member may beconducted in the presence of a binder. Preferred examples of bindersinclude methylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose and polyvinylpyrrolidone.

With respect to the method for forming, on the surface of the coremember, a coating comprising the above-mentioned coating base materialand the above-mentioned insoluble auxiliary material, there is noparticular limitation. For example, using a centrifugal rollinggranulator, a rolling fluid-bed granulator, a fluid-bed granulator orthe like, the coating can be formed as follows. First, theabove-mentioned coating base material is dissolved or dispersed in asolvent, such as water, ethanol, methylene chloride or acetone, and inthe resultant solution or dispersion, the above-mentioned insolubleauxiliary material is dispersed, to thereby obtain a coating liquid.Then, using a fluid-bed granulator or the like, the coating liquid iscoated on the surface of the core member, while evaporating the solventcontained in the coating solution coated on the core member by heatedair, to thereby obtain a sustained-release coated particle.

In the present invention, if desired, the sustained-release coatedparticle may further contain, in the core and/or coating thereof, apharmceutically acceptable excipient, binder, disintegrant, corrigent,pH-adjusting agent, lubricant, thickening agent, coloring agent or thelike.

Using the thus prepared sustained-release coated particle, the oralsustained-release preparation of the present invention can be obtainedby, for example, a method in which the sustained-release coated particleis encapsulated to thereby obtain the oral sustained-release preparationof the present invention in the form of a capsule, or a method in whichthe sustained-release coated particle is tableted to thereby obtain theoral sustained-release preparation of the present invention in the formof a tablet. Further, the sustained-release coated particle as such canalso be used as the oral sustained-release preparation of the presentinvention in this case, the sustained-release coated particle can beused in various forms, such as granule, powder and pill. With respect tothe form of the oral sustained-release preparation of the presentinvention, it is preferred that the preparation is in the form of acapsule or a granule (each of a powder and a pill is also regarded as agranule).

Further, with respect to the method for obtaining the preparation of thepresent invention in the form of a tablet, reference can be made to thedescription of Yoshiaki Kawashima et al. (“Huntai no asshuku seikeigijutsu (Method for compression-molding a powder)”, p. 172, Shinji Aokiet al., edited by the committee for Pharmaceutical Preparations andParticle Design, The Society of Powder Technology, Japan, published byThe Nikkan Kogyo Shinbun, Ltd., Japan, 1998).

The content of the active ingredient in the oral sustained-releasepreparation of the present invention may vary depending on the types andamounts of other ingredients, the indication (namely, disease-sufferingand treatment-needing patient condition) of the preparation and thelike, and, hence, is not particularly limited. For example, when thepreparation of the present invention, which can be used for thetreatment of various diseases, is used for the treatment of an ischemicdisease, such as angina pectoris, the content of the active ingredientin the preparation of the present invention per dose of the preparationis generally 1 to 1,000 mg, preferably 15 to 300 mg, in terms of theweight of fasudil hydrochloride hemihydrate.

If desired, the oral sustained-release preparation may further contain apharmceutically acceptable excipient, binder, disintegrant, corrigent,pH-adjusting agent, lubricant, thickening agent, aromatizing agent,coloring agent or the like.

The oral sustained-release preparation may comprise at least twodifferent types of sustained-release coated particles, which havedifferent sustain-release properties. Further, the oralsustained-release preparation may further comprise a rapid-releaseparticle containing the above-mentioned active ingredient. Theabove-mentioned “rapid-release particle” means a particle capable ofrapidly releasing the active ingredient. Examples of rapid-releaseparticles include the above-mentioned core members as such, e.g., thecore member composed only of the active ingredient, which can beobtained by the above-mentioned method (c); and rapid-release particlesobtained by coating such a core member in accordance with conventionalmethods or methods similar to the above-mentioned method for coating thecore member, wherein appropriate coating conditions or coating materialsare selected so as to obtain a rapid-release particle.

When the oral sustained-release preparation of the present inventioncomprises at least two different types of sustained-release coatedparticles, or contains the sustained-release coated particles and therapid-release particles, the weight ratio of the particles can bedetermined by, for example, the following method.

With respect to the oral sustained-release preparation of the presentinvention containing n different types of particles K₁, K₂ . . . K_(i) .. . K_(n), let us assume:

that the weight ratio of particle K_(i) to the total weight of particlesK₁, K₂ . . . K_(i) . . . K_(n) is defined as X_(i),

that the weight ratio of the active ingredient contained in particleK_(i) to the weight of particle K_(i) is defined as Z_(i) and

that the weight ratio of the active ingredient contained in particleK_(i) to the total weight of the active ingredients which are,respectively, contained in particles K₁, K₂ . . . K_(i) . . . K_(n)(i.e., the total weight of the active ingredients originally containedin the oral sustained-release preparation of the present invention) isdefined as Y_(i).

Then, the following relationship can be obtained:

-   -   Y ₁ :Y ₂ : . . . Y _(i) : . . . :Y _(n) =X ₁ ×Z ₁ :X ₂ ×Z ₂ : .        . . X _(i) ×Z _(i) : . . . :X _(n) ×Z _(n).        Therefore, X _(i) =Y _(i) /Z _(i)   (a).

Further, with respect to particle K_(i), by the below-described paddlemethod of the dissolution test (or a method which can be used forobtaining substantially the same results as in the paddle method), thedissolution rates (Q_(i3), Q_(i6) and Q_(i15)) of the active ingredientat the points in time of 3, 6 and 15 hours after the start of thedissolution test are measured.

Then, with respect to particles K₁, K₂ . . . K_(i) . . . K_(n), Y_(i)values satisfying all of the following requirements (I), (II) and (III)are appropriately chosen. $\begin{matrix}{5 \leqq {\sum\limits_{i = 1}^{n}{Y_{i}Q_{i\quad 3}}} \leqq 40} & (I) \\{35 \leqq {\sum\limits_{i = 1}^{n}{Y_{i}Q_{i\quad 6}}} \leqq 70} & ({II}) \\{70 \leqq {\sum\limits_{i = 1}^{n}{Y_{i}Q_{i\quad 15}}}} & ({III})\end{matrix}$

Using the obtained Y_(i) values and Z_(i) values, X_(i) values can becalculated in accordance with formula (a) above.

In this instance, it is noted that the amount of the active ingredientis defined as the weight of fasudil hydrochloride anhydride. That is, asmentioned above, when a fasudil hydrochloride hydrate is used as theactive ingredient, the weight of an equimolar amount of fasudilhydrochloride anhydride is taken as the amount of the active ingredient.

The preparation of the present invention exhibits, with respect to theactive ingredient, the following dissolution rates (1), (2) and (3), asmeasured by method 2 (paddle method) of the dissolution test describedin the Japanese Pharmacopoeia Thirteenth Edition:

(1) dissolution of 5 to 40% by weight, based on the weight of the activeingredient originally contained in the preparation, at the point in timeof 3 hours after the start of the dissolution test,

(2) dissolution of 35 to 70% by weight, based on the weight of theactive ingredient originally contained in the preparation, at the pointin time of 6 hours after the start of the dissolution test, and

(3) dissolution of 70% by weight or more, based on the weight of theactive ingredient originally contained in the preparation, at the pointin time of 15 hours after the start of the dissolution test.

The above-mentioned method 2 (hereinafter referred to simply as “paddlemethod”) of the dissolution test is described in the JapanesePharmacopoeia Thirteenth Edition (adopted since 1996) under the section“General Tests”. Hereinbelow, an explanation will be made on one modefor performing the dissolution test by the paddle method (an Englishversion of the Japanese Pharmacopoeia Thirteenth Edition (published in1996) is available from Yakuji Nippo, Ltd., Japan).

In the explanation made below, the amount of the active ingredient isdefined as the weight of fasudil hydrochloride anhydride. That is, asmentioned above, when a fasudil hydrochloride hydrate is used as theactive ingredient, the weight of an equimolar amount of fasudilhydrochloride anhydride is taken as the amount of the active ingredient.

There is no particular limitation with respect to the apparatus used forconducting the dissolution test as long as the apparatus is inconformity with the Japanese Pharmacopoeia and the dissolution test bythe paddle method.

First, 900 ml of a dissolution medium (deaerated by a suitable method)is added to a vessel of the dissolution test apparatus, and thetemperature of the dissolution medium is maintained at 37±0.5° C.Usually, when the oral sustained-release preparation of the presentinvention is subjected to the dissolution test, distilled water is usedas the dissolution medium. With respect to the method for deaerating thedissolution medium, there is no particular limitation, and thedeaeration of the dissolution medium can be conducted by placing thedissolution medium under reduced pressure, by subjecting the dissolutionmedium to ultrasonication, or by subjecting the dissolution medium toultrasonication under reduced pressure. Such a deaeration treatment isusually conducted for 5 to 10 minutes.

Next, a paddle is attached to the apparatus, and a sample of the oralsustained-release preparation of the present invention is allowed tosink to the center of the bottom of the vessel. The revolution of thepaddle is started immediately after the sample reaches the bottom of thevessel. The revolution rate of the paddle is adjusted to 100±4revolutions per minute. During the subsequent steps, the opening of thevessel is covered to prevent the evaporation of the dissolution medium.

Usually, one dose of the oral sustained-release preparation of thepresent invention is used as a sample for the dissolution test. Forexample, when the oral sustained-release preparation is in the form of atablet or a capsule, one tablet or one capsule is used as a sample. Whensuch a preparation floats in the dissolution medium, the preparation isplaced in a sinker specified in the Japanese Pharmacopoeia, and allowedto sink to the center of the bottom of the vessel. When the oralsustained-release preparation is in the form of granules, a powder andthe like, one dose of the preparation is measured and added directly tothe dissolution medium in the vessel. Usually, in this case, there is noneed to use a sinker.

At the points in time of at least 3, 6 and 15 hours, preferably 1, 2, 3,4, 6, 8, 10, 12, 15 and 20 hours after the start of the dissolution test(namely after the start of the revolution of the paddle), 10 ml of thedissolution medium containing the active ingredient released from thepreparation (hereinafter, referred to as an “active ingredient-dissolvedsolution”) is collected from the vessel at a position which isintermediate between the surface of the dissolution medium and the topof the paddle, and 10 mm distant from the inner wall of the vessel.Immediately after collecting the active ingredient-dissolved solution,10 ml of distilled water heated to 37±0.5° C. is carefully added to thevessel to thereby compensate for the dissolution medium taken from thevessel. The collected active ingredient-dissolved solution is filteredusing a membrane filter (pore size: 0.5 μm) and the resultant filtrateis used as a sample solution.

Apart from the above operation, a standard fasudil hydrochloridesolution having a known concentration of fasudil hydrochloride isprepared by dissolving a predetermined amount of a standard fasudilhydrochloride in distilled water, followed by adjusting the volume ofthe aqueous fasudil hydrochloride solution to 1,000 ml. With respect tothe sample solution and the standard fasudil hydrochloride solution, anabsorbance at 275 nm (hereinafter referred to simply as the“absorbance”) is measured.

When the 1st, 2nd, . . . and n-th (n is an integer of 3 or more) samplesolutions are respectively collected at the points in time of t₁ hr, t₂hr, . . . and t_(n) hr in the above-mentioned manner, the weight percent(%) of the dissolved active ingredient contained in the activeingredient-dissolved solution, based on the weight of the activeingredient originally contained in the preparation (hereinafter referredto simply as a “dissolution rate”) can be calculated as follows, takingas an example a dissolution rate at the point in time of collecting the1st sample solution, that is, at the point in time of t₁ hours after thestart of the dissolution test:

Dissolution rate at the point in time of t₁ hr from the start of thedissolution test (%) = 100 × {m_(s) × A₁ ÷ (A_(s) × 1000 ÷ 900) ÷ m_(t)}wherein:

-   -   m_(t): total weight of the active ingredient originally        contained in the preparation;    -   m_(s): weight of the active ingredient used for preparing the        standard solution;    -   A₁: absorbance of the 1st sample solution; and    -   A_(s): absorbance of the standard solution.

Further, the dissolution rate (%) at the point in time of collecting thei-th (i represents an integer of from 2 to n) sample solution, that is,at the point in time of t_(i) hr after the start of the dissolutiontest, can be calculated by the following formula:

Dissolution rate (%) at the point in time of t_(i) hr from the start ofthe dissolution test$= {100 \times \left\{ {m_{s} \times {{\left( {A_{i} + {\sum\limits_{j = 1}^{i - 1}{A_{j} \times {10 \div 900}}}} \right) \div \left( {A_{s} \times {1000 \div 900}} \right)} \div m_{t}}} \right\}}$

wherein:

-   -   m_(t): total weight of the active ingredient originally        contained in the preparation;    -   m_(s): weight of the active ingredient used for preparing the        standard solution;    -   A_(i): absorbance of the i-th sample solution;    -   A_(s): absorbance of the standard solution; and        $\sum\limits_{j = 1}^{i - 1}{A_{j}\text{:}}$    -   sum of the absorbances of the 1st to (i-1)-th sample solutions.

Usually, the above-mentioned test is repeated six times, and the meanvalue of the dissolution rates obtained at the point in time of t₁ hoursafter the start of the dissolution tests is determined.

As mentioned above, with respect to the oral sustained-releasepreparation of the present invention, the dissolution rates (meanvalues) of the active ingredient determined by the above-mentionedmethod at the points in time of 3, 6 and 15 hours after the start of thedissolution test satisfy the above-mentioned dissolution raterequirements (1), (2) and (3), respectively.

With respect to the oral sustained-release preparation of the presentinvention, it is preferred that the dissolution rate at the point intime of 3 hours after the start of the dissolution test is 5 to 35% byweight, based on the weight of the active ingredient originallycontained in the preparation.

Further, it is preferred that the dissolution rate at the point in timeof 6 hours after the start of the dissolution test is not lower than thedissolution rate at the point in time of 3 hours after the start of thedissolution test, and the dissolution rate at the point in time, of 15hours after the start of the dissolution test is not lower than thedissolution rate at the point in time of 6 hours after the start of thedissolution test.

Methods other than the paddle method mentioned above can be used toevaluate the dissolution rate of the active ingredient of the oralsustained-release preparation of the present invention, with the provisothat such methods provide substantially the same evaluation as obtainedby the paddle method. Examples of other methods include, method 1(rotary basket method) and method 3 (flow-through method) of theJapanese Pharmacopoeia Thirteenth Edition; a method described under thesection “Dissolution” at page 1791 of The United States PharmacopoeiaXXIII Edition (adopted since 1995), which uses “Apparatus 2”, and othermethods conducted in accordance with this method; and a method describedunder the section “2.9.3. Dissolution Test for Solid Dosage Forms” atpage 128 of the European Pharmacopoeia Third Edition (adopted since1997), which uses “Paddle apparatus”, and other methods conducted inaccordance with this method.

The oral sustained-release preparation of the present invention isorally administered. The dose of the oral sustained-release preparationof the-present invention may widely vary depending on the types and theamounts of the components of the preparation, the disease to be treatedwith the preparation, and the conditions, age and sex of the patient.When the oral sustained-release preparation of the present invention isused for treating an ischemic disease (such as angina pectoris), asuitable amount of the oral sustained-release preparation per dose isselected within the range of from 1 to 1,000 mg, preferably 15 to 300mg, in terms of the weight of fasudil hydrochloride hemihydrate, and thepreparation is orally administered to an adult patient once or twice aday or once in two days.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinbelow, the present invention will be described in more detail withreference to the following Reference Examples, Examples, ComparativeExamples and Experiments, which should not be construed as limiting thescope of the present invention.

In the following Reference Examples, Examples and Comparative Examples,in addition to fasudil hydrochloride (used as an active ingredient), thefollowing materials were used for producing pharmaceutical preparations.

1) Nucleating Excipient (Excipient in the Form of Fine Particles)

NONPAREIL 105 (spherical granules of lactose and crystalline cellulose(particle diameter: 500 to 710 μm)) (manufactured and sold by FreundIndustrial Co., Ltd., Japan).

CELPHERE CP-507 (granules of crystalline cellulose (particle diameter:500 to 710 μm)) (manufactured and sold by Asahi Kasei Kogyo KabushikiKaisha, Japan).

2) Coating Base Material

Ethylcellulose (grade: 10 cps) (manufactured and sold by Dow ChemicalCompany, USA).

Eudragit RLPO (a copolymer of ethyl acrylate/methylmethacrylate/trimethylammonioethyl methacrylate chloride) (manufacturedand sold by RÖHM GmbH, Germany).

Eudragit RSPO (a copolymer of ethyl acrylate/methylmethacrylate/trimethylammonioethyl methacrylate chloride (wherein thecontents of the comonomer units are different from those of EudragitRLPO mentioned above)) (manufactured and sold by RÖHM GmbH, Germany).

Aquacoat (an aqueous dispersion of ethylcellulose) (manufactured andsold by Asahi Kasei Kogyo Kabushiki Kaisha, Japan).

3) Insoluble Auxiliary Material

Talc (in conformity with the Japanese Pharmacopoeia; average particlediameter: 11.0 μm) (manufactured and sold by Hayashi Chemical Co., Ltd.,Japan).

Magnesium stearate (in conformity with the Japanese Pharmacopoeia;average particle diameter: 11.3 μm) (manufactured and sold by TaiheiChemical Co., Ltd., Japan).

Titanium oxide (anatase type) (manufactured and sold by Wako PureChemical Industries, Ltd., Japan).

4) Other Materials

HPC-L (hydroxypropylcellulose) (manufactured and sold by Nippon SodaCo., Ltd., Japan).

Triethyl citrate (manufactured and sold by Pfizer Pharmaceuticals Inc.,Japan).

TC-5R (hydroxypropylmethylcellulose 2910) (manufactured and sold byShin-Etsu Chemical Ind. Co., Ltd., Japan).

D-mannitol (manufactured and sold by TOWA CHEMICAL INDUSTRY CO., LTD.,Japan).

NS-300 (carmellose) (manufactured and sold by Gotoku Chemical Co., Ltd.,Japan).

AVICEL PH301 (crystalline cellulose) (manufactured and sold by AsahiKasei Kogyo Kabushiki Kaisha, Japan).

ADOSOLIDER 101 (light anhydrous silicic acid) (manufactured and sold byFreund Industrial Co., Ltd., Japan).

TC-5RW (hydroxypropylmethylcellulose 2910; a white substance obtained bydepigmenting TC-5R mentioned above) (manufactured and sold by Shin-EtsuChemical Ind. Co., Ltd., Japan).

Polishing WAX 103 (carnauba wax) (manufactured and sold by FreundIndustrial Co., Ltd., Japan).

Corn starch (manufactured and sold by NIHON SHOKU-HIN KAKO CO., LTD.,Japan).

PRIMOJEL (sodium carboxylmethylstarch) (manufactured and sold byMatsutani Chemical Industry Co., Ltd., Japan).

Ethanol (in conformity with the Japanese Pharmacopoeia) (manufacturedand sold by Wako Pure Chemical Industries, Ltd., Japan).

Capsule No. 1 (in conformity with the Japanese Pharmacopoeia)(manufactured and sold by Shionogi Qualicaps Co., Ltd., Japan).

Capsule No. 2 (in conformity with the Japanese Pharmacopoeia)(manufactured and sold by Shionogi Qualicaps Co., Ltd., Japan).

Capsule No. 3 (in conformity with the Japanese Pharmacopoeia)(manufactured and sold by Shionogi Qualicaps Co., Ltd., Japan).

In the Experiments described below, the concentration of the drug in theblood of rats was determined by the below-mentioned method using highperformance liquid chromatography (HPLC). Illustratively stated, asample for HPLC was prepared as described in item (1) below, and HPLCwas performed under the conditions described in item (2) below. By thebelow-mentioned method, only 1-hydroxy derivative of fasudilhydrochloride (i.e., active metabolite) was detected, and othermetabolites or unchanged fasudil hydrochloride was not detected.

(1) Preparation of a Sample for HPLC

1 ml of blood was collected from a rat and subjected to centrifugationto thereby obtain a supernatant (i.e., plasma). The obtained plasma wasdiluted with 8 ml of distilled water, and the diluted plasma was appliedto a solid-phase extraction column (Bond Elut CBA; manufactured and soldby GL Sciences Inc., Japan) which had previously been conditioned firstwith 3 ml of methanol and then with 3 ml of distilled water. Then, thecolumn was washed first with 3 ml of distilled water and then with 9 mlof methanol, to thereby elute most of substances other than the activemetabolite. Subsequently, the column was washed with 4 ml of methanolcontaining 2% of concentrated ammonia water, thereby obtaining afraction containing the active metabolite. The obtained fraction wasevaporated to dryness by means of a centrifugal evaporator, and theresultant solid was dissolved in 200 μl of a mixture of 50 mM phosphatebuffer (pH 6.8) and methanol (phosphate buffer:methanol=9:1 (v/v)),thereby obtaining a solution. The solution was subjected to filtrationusing a filter, and the resultant filtrate was used as an HPLC sample.

(2) Apparatus and Conditions for HPLC

Apparatus: D7000 model HPLC system (manufactured and sold by Hitachi,Ltd., Japan)

Column: YMC AM-302 (manufactured and sold by YMC Co., Ltd., Japan)

Column temperature: 30° C.

Mobile phase: a mixture of 50 mM phosphate buffer (pH 6.8) andacetonitrile (phosphate buffer:acetonitrile=85:15 (v/v))

Flow rate: 0.5 ml/min.

UV detector: L-7400 model UV detector (manufactured and sold by Hitachi,Ltd., Japan)

Detection wavelength: 300 nm

Volume of a sample applied: 100 μl

REFERENCE EXAMPLE 1

400 g of fasudil hydrochloride anhydride was dissolved in 600 ml ofpurified water to obtain an aqueous solution of fasudil hydrochloride.Using the obtained aqueous solution of fasudil hydrochloride, 350 g ofNONPAREIL 105 was subjected to coating with fasudil hydrochloride by theWurster method in the following manner. That is, 350 g of NONPAREIL 105was charged into a LAB-1 model fluid-bed granulator (manufactured andsold by POWREX CORPORATION, Japan), which was equipped with a sprayer.The aqueous solution of fasudil hydrochloride was charged in the sprayerof the granulator. The NONPAREIL 105 was subjected to fluidization inthe granulator under conditions wherein the air temperature was 80° C.and the air flow rate was 50 m³/hr, while spraying the aqueous solutionof fasudil hydrochloride into the fluid-bed of NONPAREIL 105 underconditions wherein the spraying rate was 2 ml/min and the air pressurefor spraying was 2 kg/cm² so as to coat the NONPAREIL 105 with fasudilhydrochloride, thereby obtaining 710 g of core member particles eachhaving a particle diameter of from 600 μm to 850 μm. The same procedureas mentioned above was conducted thrice in total, so that 3 lots of thecore members having a total weight of approximately 2,000 g wereobtained.

REFERENCE EXAMPLE 2

The preparation of core member particles was conducted in substantiallythe same manner as in Reference Example 1 except that 400 g of fasudilhydrochloride hemihydrate was used instead of 400 g of fasudilhydrochloride anhydride and 350 g of CELPHERE CP-507 was used instead of350 g of NONPAREIL 105, thereby obtaining 700 g of core member particleseach having a particle diameter of from 600 μm to 850 μm. The sameprocedure as mentioned above was conducted thrice in total, so that 3lots of the core members having a total weight of approximately 2,000 gwere obtained.

REFERENCE EXAMPLE 3

1,400 g of fasudil hydrochloride hemihydrate and 70 g of HPC-L weredissolved in 2,100 ml of purified water to obtain an aqueous solution offasudil hydrochloride. Using the obtained aqueous solution of fasudilhydrochloride, 700 g of CELPHERE CP-507 was subjected to coating withfasudil hydrochloride in the following manner. That is, 700 g ofCELPHERE CP-507 was charged into an MP-01 model rolling fluid-bedgranulator (manufactured and sold by POWREX CORPORATION, Japan), whichwas equipped with a sprayer. The aqueous solution of fasudilhydrochloride was charged in the sprayer of the granulator. The CELPHERECP-507 was subjected to fluidization in the granulator under conditionswherein the air temperature was 85° C., the air flow rate was 70 m³/hrand the revolution rate of the rotor was 400 rpm, while spraying theaqueous solution of fasudil hydrochloride into the fluid-bed of CELPHERECP-507 under conditions wherein the spraying rate was 8 g/min and theair pressure for spraying was 0.3 MPa/cm² so as to coat the CELPHERECP-507 with fasudil hydrochloride, thereby obtaining 2,155 g of coremember particles each having a particle diameter of from 710 μm to 1,000μm.

EXAMPLE 1

12 g of ethylcellulose was dissolved in 300 ml of ethanol to therebyobtain a solution. 36 g of talc was dispersed in the obtained solutionto thereby prepare a coating dispersion. Using the obtained coatingdispersion, 200 g of the core member produced in Reference Example 1 wassubjected to coating with ethylcellulose and talc by the Wurster methodin the following manner. That is, 200 g of the core member produced inReference Example 1 was charged into a LAB-1 model fluid-bed granulator(manufactured and sold by POWREX CORPORATION, Japan), which was equippedwith a sprayer. The coating dispersion was charged in the sprayer of thegranulator. The core member produced in Reference Example 1 wassubjected to fluidization in the granulator under conditions wherein theair temperature was 50° C. and the air flow rate was 50 m³/hr, whilespraying the coating dispersion into the fluid-bed of the core memberunder conditions wherein the spraying rate was 5 ml/min and the airpressure for spraying was 2 kg/cm so as to coat the core member withethylcellulose and talc, thereby obtaining sustained-release coatedparticles each having a particle diameter of from 600 to 1,000 Rm. Theobtained sustained-release coated particles were filled into No. 3capsules in an amount of 185 mg per capsule, to thereby obtain an oralsustained-release preparation containing 80 mg of fasudil hydrochloride(in terms of the weight of fasudil hydrochloride anhydride).

EXAMPLE 2

The preparation of sustained-release coated particles was conducted insubstantially the same manner as in Example 1 except that the coremember produced in Reference Example 2 was used instead of the coremember produced in Reference Example 1 and the amount of talc waschanged to 60 g, thereby obtaining sustained-release coated particleseach having a particle diameter of from 600 μm to 1,000 μm. The obtainedsustained-release coated particles were filled into No. 2 capsules in anamount of 215 mg per capsule, to thereby obtain an oralsustained-release preparation containing 80 mg of fasudil hydrochloride(in terms of the weight of fasudil hydrochloride hemihydrate).

EXAMPLE 3

The preparation of sustained-release coated particles was conducted insubstantially the same manner as in Example 2 except that the amount ofthe core member produced in Reference Example 2 was changed to 130 g,the amount of ethylcellulose was changed to 8 g, the amount of talc waschange to 24 g, the air flow rate for fluidizing the core member waschanged to 40 m³/hr and the spraying rate of the coating dispersion waschanged to 4 ml/min, thereby obtaining sustained-release coatedparticles each having a particle diameter of from 600 μm to 1,000 μm.The obtained sustained-release coated particles were filled into No. 3capsules in an amount of 200 mg per capsule, to thereby obtain an oralsustained-release preparation containing 80 mg of fasudil hydrochloride(in terms of the weight of fasudil hydrochloride hemihydrate).

EXAMPLE 4

The preparation of sustained-release-coated particles was conducted insubstantially the same manner as in Example 1 except that the followingconditions were used. 14.3 g of Eudragit RSPO was dissolved in 125 ml ofethanol to thereby obtain a solution. 42.9 g of talc was dispersed inthe obtained solution to thereby prepare a coating dispersion. The thusprepared coating dispersion was used instead of the coating dispersionused in Example 1. In addition, the core member produced in ReferenceExample 1 was used in an amount of 190 g, instead of 200 g used inExample 1. By the above procedure, sustained-release coated particleseach having a particle diameter of from 600 μm to 1,000 μm wereobtained. The obtained sustained-release coated particles were filledinto No. 3 capsules in an amount of 194 mg per capsule, to therebyobtain an oral sustained-release preparation containing 80 mg of fasudilhydrochloride (in terms of the weight of fasudil hydrochlorideanhydride).

EXAMPLE 5

The preparation of sustained-release coated particles was conducted insubstantially the same manner as in Example 1 except that 11.4 g ofmagnesium stearate was used instead of talc, the amount ofethylcellulose was changed to 11.4 g, the volume of ethanol was changedto 285 ml and the amount of the core member produced in ReferenceExample 1 was changed to 190 g, thereby obtaining sustained-releasecoated particles each having a particle diameter of from 600 μm to 1,000μm. The obtained sustained-release coated particles were filled into No.3 capsules in an amount of 167 mg per capsule, to thereby obtain an oralsustained-release preparation containing 80 mg of fasudil hydro-chloride(in terms of the weight of fasudil hydrochloride anhydride).

EXAMPLE 6

Substantially the same procedure for producing sustained-release coatedparticles as in Example 2 was repeated except that the followingconditions were used. 33 g of triethyl citrate and 100 g of magnesiumstearate were added to 333 g of Aquacoat, and the resultant mixture wasdiluted with 350 ml of distilled water to thereby prepare a coatingdispersion. The thus prepared coating dispersion was used instead of thecoating dispersion used in Example 2. In addition, the air temperaturein the granulator was 70° C. (instead of 50° C. used in Example 2) andthe spraying rate of the coating dispersion was 2 ml/min (instead of 5ml/min used in Example 2). By the above procedure, spray-coatedparticles were obtained. The obtained spray-coated particles were driedat 80° C. for 12 hrs to thereby obtain sustained-release coatedparticles each having a particle diameter of from 710 μm to 1,180 μm.The obtained sustained-release coated particles were filled into No. 1capsules in an amount of 340 mg per capsule, to thereby obtain an oralsustained-release preparation containing 80 mg of fasudil hydrochloride(in terms of the weight of fasudil hydrochloride hemihydrate).

EXAMPLE 7

The preparation of sustained-release coated particles was conducted insubstantially the same manner as in Example 1 except that the followingconditions were used. 1.5 g of Eudragit RLPO and 13.5 g of Eudragit RSPOwere dissolved in 250 ml of ethanol to thereby obtain a solution. 45 gof talc was dispersed in the obtained solution to thereby prepare acoating dispersion. The thus prepared coating dispersion was usedinstead of the coating dispersion used in Example 1. By the aboveprocedure, sustained-release coated particles each having a particlediameter of from 600 μm to 1,000 μm were obtained. The obtainedsustained-release coated particles were filled into No. 3 capsules in anamount of 194 mg per capsule, to thereby obtain an oralsustained-release preparation containing 80 mg of fasudil hydrochloride(in terms of the weight of fasudil hydrochloride anhydride).

EXAMPLE 8

Substantially the same procedure for producing sustained-release coatedparticles as in Example 2 was repeated except that the followingconditions were used. 2 g of TC-5R was dissolved in 50 ml of a mixtureof water and ethanol (the water/ethanol volume ratio was 1/1) to therebyobtain a solution. The thus obtained solution was used as a coatingsolution, instead of the coating dispersion used in Example 2. Inaddition, the spraying rate of the coating solution was 3 ml/min(instead of 5 ml/min used in Example 2). By the above procedure, coatedparticles A were obtained each having a particle diameter of from 600 μmto 850 μm and containing 50% by weight of fasudil hydrochloride (interms of the weight of fasudil hydrochloride hemihydrate) (hereinafter,the coated particles A are referred to simply as “particles A”).

On the other hand, the preparation of sustained-release coated particleswas conducted in substantially the same manner as in Example 2 exceptthat the following conditions were used. 2.25 g of Eudragit RLPO and20.25 g of Eudragit RSPO were dissolved in 375 ml of ethanol to therebyobtain a solution. 67.5 g of talc was dispersed in the obtained solutionto thereby prepare a coating dispersion. The thus prepared coatingdispersion was used instead of the coating dispersion used in Example 2.By the above procedure, sustained-release coated particles B wereobtained each having a particle diameter of from 600 μm to 1,000 μm andcontaining 35% by weight of fasudil hydrochloride (in terms of theweight of fasudil hydrochloride hemihydrate) (hereinafter, thesustained-release coated particles B are referred to simply as“particles B”).

32 g of the above-obtained particles A and 183 g of the above-obtainedparticles B (wherein these weights correspond, respectively, to 2 partsby weight and 8 parts by weight in terms of the weight of fasudilhydrochloride hemihydrate) were uniformly mixed to thereby obtain mixedparticles. 215 mg of the obtained mixed particles were filled into No. 2capsules, to thereby obtain an oral sustained-release preparationcontaining 80 mg of fasudil hydrochloride (in terms of the weight offasudil hydrochloride hemihydrate).

EXAMPLE 9

The preparation of sustained-release coated particles was conducted insubstantially the same manner as in Example 2 except that 300 g of thecore member produced in Reference Example 3 was used instead of the coremember produced in Reference Example 2, the amount of ethylcellulose waschanged to 18 g and the amount of talc was changed to 18 g, therebyobtaining sustained-release coated particles each having a particlediameter of from 850 μm to 1,180 μm. The obtained sustained-releasecoated particles were filled into No. 3 capsules in an amount of 143 mgper capsule, to thereby obtain an oral sustained-release preparationcontaining 80 mg of fasudil hydrochloride (in terms of the weight offasudil hydrochloride hemihydrate).

EXAMPLE 10

18 g of ethylcellulose was dissolved in 306 ml of ethanol to therebyobtain a solution. 90 g of talc was dispersed in the obtained solutionto thereby prepare a coating dispersion. Using the obtained coatingdispersion, 400 g of the core member produced in Reference Example 3 wassubjected to coating with ethylcellulose and talc in the followingmanner. That is, 400 g of the core member produced in Reference Example3 was charged into an SFC-MINI model rolling fluid-bed granulator(manufactured and sold by Freund Industrial Co., Ltd., Japan), which wasequipped with a sprayer. The coating dispersion was charged in thesprayer of the granulator. The core member produced in Reference Example3 was subjected to fluidization in the granulator under conditionswherein the air temperature was 40° C., the fluidization air flow ratewas 0.3 m³/min, the slit air flow was 0.3 m³/min and the revolution rateof the rotor was 800 rpm, while spraying the coating dispersion into thefluid-bed of the core member under conditions wherein the spraying ratewas 8 ml/min and the air pressure for spraying was 2 kg/cm² so as tocoat the core member with ethylcellulose and talc, thereby obtainingsustained-release coated particles each having a particle diameter offrom 850 to 1,180 μm. The obtained sustained-release coated particleswere filled into No. 3 capsules in an amount of 158 mg per capsule, tothereby obtain an oral sustained-release preparation containing 80 mg offasudil hydrochloride (in terms of the weight of fasudil hydrochlorideanhydride).

EXAMPLE 11

The preparation of sustained-release coated particles was conducted insubstantially the same manner as in Example 10 except that the amount ofethylcellulose was changed to 20 g, the amount of talc was changed to100 g and the volume of ethanol was changed to 340 ml, thereby obtainingsustained-release coated particles each having a particle diameter offrom 850 μm to 1,180 μm. The obtained sustained-release coated particlesas such were packed, as a granular oral sustained-release preparation,in packages in an amount of 163 mg per package. The oralsustained-release preparation contained 80 mg of fasudil hydrochloride(in terms of the per-package weight of fasudil hydrochloridehemihydrate).

COMPARATIVE EXAMPLE 1

Substantially the same procedure for producing sustained-release coatedparticles as in Example 1 was repeated except that talc was not used,thereby obtaining coated particles each having a particle diameter offrom 600 μm to 1,000 μm. The obtained coated particles were filled intoNo. 2 capsules in an amount of 200 mg per capsule, to thereby obtain anoral capsule preparation containing fasudil hydrochloride.

COMPARATIVE EXAMPLE 2

Substantially the same procedure for producing sustained-release coatedparticles as in Example 2 was repeated except that a coating solutionobtained by dissolving 3 g of Eudragit RLPO and 27 g of Eudragit RSPO in500 ml of ethanol was used instead of the coating dispersion used inExample 2, thereby obtaining coated particles each having a particlediameter of from 600 μm to 1,000 μm. The obtained coated particles werefilled into No. 2 capsules in an amount of 200 mg per capsule, tothereby obtain an oral capsule preparation containing fasudilhydrochloride.

COMPARATIVE EXAMPLE 3

Substantially the same procedure for producing sustained-release coatedparticles as in Example 6 was repeated except that magnesium stearatewas not used, the amount of triethyl citrate was changed to 33.5 g andthe volume of distilled water was changed to 300 ml, thereby obtainingcoated particles each having a particle diameter of from 600 μm to 1,000μm. The obtained coated particles were filled into No. 2 capsules in anamount of 200 mg per capsule, to thereby obtain an oral capsulepreparation containing fasudil hydrochloride.

COMPARATIVE EXAMPLE 4

Substantially the same procedure for producing the sustained-releasecoated particles as in Example 4 was repeated except that a dispersionobtained by dispersing 172.5 g of talc in a solution obtained bydissolving 11.5 g of Eudragit RSPO in 400 ml of ethanol was used as thecoating dispersion, thereby obtaining coated particles each having aparticle diameter of from 600 to 1,000 μm. The obtained coated particleswere filled into No. 2 capsules in an amount of 200 mg per capsule, tothereby obtain an oral capsule preparation containing fasudilhydrochloride.

COMPARATIVE EXAMPLE 5

80 g of fasudil hydrochloride anhydride, 360 g of D-mannitol, 28 g ofNS-300, 12 g of HPC-L, 120 g of AVICEL PH301, 4 g of ADOSOLIDER 101 and3.2 g of magnesium stearate were mixed with each other and then,compression-molded by means of a dry granulator Roller Compactor Mini(manufactured and sold by Freund Industrial Co., Ltd., Japan) to therebyobtain granules. The obtained granules were sieved to thereby collectgranules having a predetermined size. The collected granules were mixedwith 4.8 g of magnesium stearate and the resultant granules fortableting were charged into a CP-12 model rotary tableting machine(manufactured and sold by Kikusui Seisakusho Ltd., Japan) and subjectedto tableting to thereby obtain uncoated tablets each having a weight of153 mg.

19.6 g of TC-5RW and 2.8 g of ethylcellulose were dissolved in 375 ml ofa mixture of purified water and ethanol (purified water:ethanol=1:4(volume ratio)) to thereby obtain a solution. Then, 5.6 g of titaniumoxide (anatase type) was dispersed in the obtained solution, therebyobtaining a coating dispersion. Using the obtained coating dispersion,the above-obtained uncoated tablets were subjected to coating in thefollowing manner. That is, the uncoated tablets were charged into aDRC-300 model coating machine (manufactured and sold by POWREXCORPORATION, Japan) which was equipped with a sprayer. The coatingdispersion was charged into the sprayer of the coating machine. Theabove-obtained uncoated tablets were subjected to fluidization in thecoating machine under conditions wherein the air temperature was 80° C.and the air flow rate was 1.2 m³/min, while spraying the coatingdispersion into the fluid-bed of the uncoated tablets so as to coat theuncoated tablets, thereby obtaining coated tablets.

Subsequently, the obtained coated tablets are subjected to polishingtreatment in the coating machine in the following manner. Approximately0.13 g of Polishing WAX 103 was charged into the coating machine, andthe rolling of the tablets was conducted in the coating machine for 30minutes while feeding heated air (temperature: 60° C.) into the coatingmachine. Then, the feeding of heated air was stopped, but the rolling ofthe tablets was continued for further 30 minutes, thereby obtainingtablet preparations each having a weight of 160 mg.

Further, substantially the same procedure as described above wasrepeated except that fasudil hydrochloride hemihydrate was used in anamount of 82.2 g (that is, 80 g in terms of the weight of fasudilhydrochloride anhydride) instead of fasudil hydrochloride anhydride,thereby obtaining tablet preparations each having a weight of 160.6 mg.

COMPARATIVE EXAMPLE 6

822 g of fasudil hydrochloride hemihydrate, 3078 g of D-mannitol and1,000 g of corn starch were charged into an FLO-15 model fluid-bedgranulator equipped with a sprayer (manufactured and sold by FreundIndustrial Co., Ltd., Japan) and then, subjected to fluidization in thegranulator, while spraying (by the top spraying method) an aqueoussolution of HPC-L (obtained by dissolving 120 g of HPC-L in 2480 g ofpurified water) into the fluid-bed in the sprayer, thereby obtaininggranules. The obtained granules were dried in the granulator. Theobtained dried granules were mixed with 120 g of Primojel (as adisintegrant) and 60 g of magnesium stearate (as a lubricant) to therebyobtain granules for tableting. The obtained granules for tableting werecharged into a CP-12 model rotary tableting machine (manufactured andsold by Kikusui Seisakusho Ltd., Japan) and subjected to tableting tothereby obtain uncoated tablets each having a weight of 130 mg.

220 g of TC-5RW was dissolved in 3600 ml of purified water to therebyobtain a solution, and 60 g of titanium oxide was dispersed in theobtained solution, thereby obtaining a coating dispersion. Using thecoating dispersion, the above-obtained uncoated tablets were subjectedto coating in the following manner. That is, the uncoated tablets werecharged into a DRC-650 model coating machine (manufactured and sold byPOWREX CORPORATION, Japan) which was equipped with a sprayer. Thecoating dispersion was charged into the sprayer of the coating machine.

The above-obtained uncoated tablets were subjected to fluidization inthe coating machine under conditions wherein the air temperature was 80°C. and the air flow rate was 6 m³/min, while spraying the coatingdispersion into the fluid-bed of the uncoated tablets so as to coat theuncoated tablets, thereby obtaining coated tablets.

Subsequently, the obtained coated tablets were subjected to polishingtreatment in the coating machine in the following manner. Approximately1.3 g of Polishing WAX 103 was charged into the coating machine, and therolling of the tablets in the coating machine was conducted in thecoating machine for 30 minutes while feeding heated air (temperature:60° C.) into the coating machine. Then, the feeding of heated air wasstopped, but the rolling of the tablets was continued for further 30minutes, thereby obtaining tablet preparations each having a weight of137 mg.

Further, substantially the same procedure as described above wasrepeated except that 800 g of fasudil hydrochloride anhydride was usedinstead of fasudil hydrochloride hemihydrate, thereby obtaining tabletpreparations each having a weight of 136.5 mg.

Experiment 1

The oral sustained-release preparations produced in Examples 1 to 11,the oral capsule preparations produced in Comparative Examples 1 to 4and the tablet preparations produced in Comparative Examples 5 and 6were each subjected to the dissolution test in accordance with method 2(paddle method) of the dissolution test described in the JapanesePharmacopoeia Thirteenth Edition for measuring a dissolution rate of anactive ingredient from the preparation. The method for the test isexplained below. In the explanation made below, the amount of the activeingredient is defined as the weight of fasudil hydrochloride anhydride.That is, as mentioned above, when a fasudil hydrochloride hydrate isused as the active ingredient, the weight of an equimolar amount offasudil hydrochloride anhydride is taken as the amount of the activeingredient.

A DT-610 model dissolution test apparatus (which is manufactured andsold by Japan Spectroscopic Co., Ltd., Japan and is in conformity withthe Japanese Pharmacopoeia) was used for the dissolution test.

Distilled water (deaerated by ultrasonication under reduced pressure(using an aspirator) for 10 minutes) was used as a dissolution medium.

First, 900 ml of the dissolution medium was added to a vessel of thedissolution test apparatus, and the temperature of the dissolutionmedium was maintained at 37±0.5 ° C.

Next, a paddle was attached to the apparatus, and a sample of theabove-mentioned preparation was placed in the sinker and allowed to sinkto the center of the bottom of the vessel (with respect to the oralsustained-release preparation produced in Example 11, 163 mg(corresponding to one dose) of the preparation was allowed to directlysink to the center of the bottom of the vessel without using thesinker). The revolution of the-paddle was started immediately after thesample reached the bottom of the vessel. The revolution rate of thepaddle was adjusted to 100±4 revolutions per minute. During thesubsequent steps, the opening of the vessel was covered to prevent theevaporation of the dissolution medium.

At the points in time of 1, 2, 3, 4, 6, 8, 10, 12, 15 and 20 hours afterthe start of the dissolution test (namely, after the start of therevolution of the paddle), 10 ml of the dissolution medium containingthe active ingredient released from the preparation (hereinafterreferred to as an “active ingredient-dissolved solution”) was collectedfrom the vessel at a position which is intermediate between the surfaceof the dissolution medium and the top of the paddle, and 10 mm distantfrom the inner wall of the vessel. Immediately after collecting theactive ingredient-dissolved solution, 10 ml of distilled water heated to37±0.5° C. was carefully added to the vessel to thereby compensate forthe dissolution medium taken from the vessel. The collected activeingredient-dissolved solution was filtered using a membrane filter(Omunipore membrane Milex LH (diameter: 25 mm, pore size: 0.5 μm);manufactured and sold by Japan Milipore Co., Ltd., Japan) and theresultant filtrate was used as a sample solution.

The sample solutions prepared from the active ingredient-dissolvedsolutions respectively collected at the points in time of 1, 2, 3, 4, 6,8, 10, 12, 15 and 20 hours after the start of the dissolution test arereferred to as “the 1st, 2nd, . . . and 10th sample solutions”,respectively.

Apart from the above operation, a standard fasudil hydrochloridesolution was prepared by dissolving a 80 mg of a standard fasudilhydrochloride (which had been weighed precisely) in distilled water,followed by adjusting the volume of the aqueous fasudil hydrochloridesolution to 1,000 ml. With respect to the sample solution and thestandard fasudil hydrochloride solution, an-absorbance at 275 nm(hereinafter referred to simply as the “absorbance”) was measured.

The dissolution rate (%) of the active ingredient at the point in timeof collecting the 1st sample solution, that is, at the point in time of1 hour after the start of the dissolution test, based on the weight ofthe active ingredient originally contained in the preparation(hereinafter, referred to simply as a “dissolution rate”), wascalculated by the following formula:

Dissolution rate (%) at the point in time of collecting the 1st samplesolution  = 100 × {m_(s) × A₁ ÷ (A_(s) × 1000 ÷ 900) ÷ m_(t)}wherein:

-   -   m_(t): total weight of the active ingredient originally        contained in the preparation;    -   m_(s): weight of the active ingredient used for preparing the        standard solution;    -   A₁: absorbance of the 1st sample solution; and    -   A_(s): absorbance of the standard solution.

Further, the dissolution rate (%) at the point in time of collecting thei-th (i represents an integer of from 2 to 10) sample solution, that is,at the point in time of t_(i) hours after the start of the dissolutiontest, based on the weight of the active ingredient originally containedin the preparation, was calculated by the following formula:

Dissolution rate at the point in time of ti hours from the start of thedissolution test (%)$= {100 \times \left\{ {m_{s} \times {{\left( {A_{i} + {\sum\limits_{j = 1}^{i - 1}{A_{j} \times {10 \div 900}}}} \right) \div \left( {A_{s} \times {1000 \div 900}} \right)} \div m_{t}}} \right\}}$

wherein:

-   -   m_(t): total weight of the active ingredient originally        contained in the preparation;    -   m_(s): weight of the active ingredient used for preparing the        standard solution;    -   A_(i): absorbance of the i-th sample solution;    -   A_(s): absorbance of the standard solution; and        $\sum\limits_{j = 1}^{i - 1}{A_{j}\text{:}}$    -   sum of the absorbances of the 1st to (i-1)-th sample solutions.

The above-mentioned test was repeated six times and the mean of thedissolution rates obtained at the point in time of i hours after thestart of the dissolution test was determined.

The results are shown in Table 1. TABLE 1 Coating basematerial:insoluble auxiliary Dissolution Rate(%) Preparation material* 1hr 3 hrs 6 hrs 15 hrs Example 1 1:3 6 34 59 94 Example 2 1:5 3 21 49 88Example 3 1:3 3 34 64 93 Example 4 1:3 4 7 36 93 Example 5 1:1 3 22 4982 Example 6 1:3 0 27 58 90 Example 7 1:3 5 11 42 97 Example 8  1:3** 2023 37 72 Example 9 1:1 4 22 50 89 Example 10 1:5 5 22 52 96 Example 111:5 3 17 45 90 Comparative 1:0 50 82 90 98 Example 1 Comparative 1:0 8393 94 95 Example 2 Comparative 1:0 13 63 81 96 Example 3 Comparative 1:15 1 5 25 53 Example 4 Comparative None*** 100 — — — Example 5Comparative None*** 100 — — — Example 6*The weight ratio of insoluble auxiliary material in each coating of thesustained-release particles was given on the assumption that the weightof the coating base material is 1.**The ratio of insoluble auxiliary material in B particles is shown,since A particles do not contain the insoluble auxiliary material.***Preparations of Comparative Examples 5 and 6 do not containsustained-release particles although each of preparations of ComparativeExamples 5 and 6 is a tablet coated with a layer containing an insolubleauxiliary material.

As shown in Table 1, with respect to each of the sustained-releasepreparations of the present invention, produced in Examples 1 to 11(each of which contains the sustained-release coated particle having acoating containing the insoluble auxiliary material), the amounts of theactive ingredient released from the preparation at the points in time of3, 6 and 15 hours after the start of the test were 5 to 35% by weight,35 to 65% by weight, and 70% by weight or more, respectively.

On the other hand, with respect to each of the capsule preparationsproduced in Comparative Examples 1 to 3 (each of which contains thecoated particle having a coating which does not contain the insolubleauxiliary material), 50% by weight or more of the active ingredient wasquickly released from the preparation within 3 hours after the start ofthe test.

With respect to the capsule preparation produced in Comparative Example4, although the preparation contained coated particles having a coatingcontaining the insoluble auxiliary material, the release of the activeingredient was extremely slow. The reason for such slow release isconsidered to be that the amount of the insoluble auxiliary materialcontained in the coating was too large.

Further, each of the preparations produced in Comparative Examples 5 and6 is a tablet coated with a layer containing the insoluble auxiliarymaterial; however, each of the preparations does not contain thesustained-release coated particle. As in the case of the capsulepreparations of Comparative Examples 1 to 3, in Comparative Examples 5and 6, the active ingredient was quickly released from each of thepreparations within 3 hours after the start of the test.

From the above, it is apparent that, for controlling the release of anactive ingredient from a preparation containing fasudil hydrochloride ora hydrate thereof as the active ingredient, it is necessary that thepreparation contain the sustained-release coated particle having thecoating containing an insoluble auxiliary material.

Experiment 2

In order to evaluate the oral sustained-release preparation of thepresent invention with respect to the sustained-release ability of theactive ingredient in the lower portion of the digestive tract (in whichthe amount of the internal liquid of the digestive tract is small), adissolution test was conducted using a dissolution medium only in asmall amount. The method of this dissolution test is explained below. Inthe explanation made below, the amount of the active ingredient isdefined as the weight of fasudil hydrochloride anhydride. That is, asmentioned above, when a fasudil hydrochloride hydrate is used as theactive ingredient, the weight of an equimolar amount of fasudilhydrochloride anhydride is taken as the amount of the active ingredient.

As a dissolution test apparatus, an apparatus comprising a reservoir, aconstant flow pump and a cell (each of which is described below) wasused, wherein the reservoir, constant flow pump and cell were connectedin this order so that a dissolution medium in the reservoir wasintroduced into the cell by means of the constant flow pump.

Reservoir: Terumo Syringe SS-10S (internal volume: 10 ml; manufacturedand sold by Terumo Corp., Japan)

Constant flow pump: 230P model pump (which is capable of transferring aliquid at an extremely low flow rate) (manufactured and sold by KDScientific Inc., U.S.A.) (hereinafter referred to simply as the “pump”)

Cell: The cylinder part of Terumo Syringe SS-01P (internal volume: 1 ml)(manufactured and sold by Terumo Corp., Japan) was cut to thereby obtaina cylinder having a length of 23 mm. A gasket (specifically, a rubberpacking fitted on the forward end of the piston of the above-mentionedsyringe) was inserted into each end of the obtained cylinder so that thedistance between the two gaskets became 15.5 mm, to thereby form a space(between the gaskets) having a volume of approximately 0.5 ml. The thusobtained cylinder having two gaskets inserted into both ends was used asthe cell.

With respect to each of the above-mentioned gaskets, a through-hole wasformed at the center thereof, and two silicone tubes for liquid transfer(length: 10 cm, inner diameter: 1 mm, outer diameter: 3 mm) were,respectively, inserted into the cylinder through the through-holes ofthe gaskets.

One of these two silicone tubes was connected to the pump, so that thedissolution medium was able to be introduced into the cell by means ofthe pump through one silicone tube, and the introduced dissolutionmedium was able to be discharged from the cell through the othersilicone tube which was not connected to the pump. Hereinafter, theexpression “discharged from the cell” means being “discharged from thecell through the silicone tube which was not connected to the pump”.

The thus obtained dissolution test apparatus was placed in a constanttemperature room in which the room temperature was 37±0.5° C. Thedissolution test was conducted in accordance with method 3 (flow-throughcell method) of the dissolution test described in the JapanesePharmacopoeia Thirteenth Edition.

Two circular filter papers (each having a diameter of 6 mm) and 183 mgof the sustained-release coated particles (before being filled in acapsule) produced in Example 2 were placed in the cell of thedissolution test apparatus so that the particles were placed between thetwo filter papers. The circular filter papers were used for preventingthe particles from flowing out of the cell.

A dissolution medium (distilled water, 37° C.) was placed in thereservoir, and transferred to and introduced into the cell (containingthe sustained-release coated particles of the present invention) bymeans of the pump at a flow rate of 0.4 ml/hr. During the period of fromthe start of the introduction of the dissolution medium to the point intime of 1 hour after the start of the introduction of the dissolutionmedium, the resultant solution, containing the active ingredientreleased from the preparation (hereinafter referred to as the “activeingredient-dissolved solution”), discharged from the cell was collectedin a 10 ml flask (that is, a 1-hour sampling was conducted). The same1-hour sampling of the active ingredient-dissolved solution as mentionedabove-was successively conducted 20 times in total. Each of the 20active ingredient-dissolved solutions respectively obtained in smallamounts as obtained using 0.4 ml/hr of dissolution medium by the 20-time1-hour sampling was diluted to 10 ml, and each of the resultant diluted,active ingredient-dissolved solutions was further diluted 100-fold,thereby obtaining 20 sample solutions.

Hereinafter, a sample solution prepared from the activeingredient-dissolved solution collected during the period of from thepoint in time of (i-i) hour(s) after the start of the dissolution testto the point in time of i hours after the start of the dissolution test(wherein i represents an integer of from 1 to 20) is referred to as the“i-th sample solution”.

80 mg of standard fasudil hydrochloride was accurately weighed anddissolved in distilled water so that the resultant solution had a volumeof 100 ml. 1 ml of the obtained solution was diluted 100-fold, therebyobtaining a standard solution of fasudil hydrochloride. With respect toeach of the sample solutions and the standard solution, the absorbanceat a wavelength of 275 nm (hereinafter referred to simply as the“absorbance”) was measured.

The weight percent (%) of the dissolved active ingredient at the end ofthe 1-hour sampling for obtaining the active ingredient-dissolvedsolution used for preparing the i-th sample solution, based on theweight of the active ingredient originally contained in the preparation(hereinafter referred to simply as the “dissolution rate”) wascalculated by the following formula.

Dissolution rate (weight %) at the end of the 1-hour sampling forobtaining the active ingredient-dissolved solution used for preparingthe i-th sample solution$= {100 \times {\left\{ {\left( {m_{s} \times {\sum\limits_{j = 1}^{i}A_{j}}} \right) \div \left( {A_{s} \times 10} \right)} \right\} \div m_{t}}}$wherein the meanings of the characters are as follows:

-   -   m_(t): the total weight of the active ingredient originally        contained in the preparation;    -   m_(s): the weight of the active ingredient used for preparing        the standard solution;    -   A_(s): the absorbance of the standard solution; and        $\sum\limits_{j = 1}^{i}{A_{j}\text{:}}$    -   the sum of the absorbances of the 1st to i-th sample solutions.

The results of the calculation are shown in Table 2 (see the item“Dissolution test using a small amount of dissolution medium”).

For comparison, Table 2 also shows the results of the dissolution test(see Experiment 1) in which the sustained-release capsule preparationproduced in Example 2 was subjected to a testing according to the paddlemethod (see the item “Paddle method”). TABLE 2 Dissolution rate (% byweight) 1 hr 2 hrs 3 hrs 4 hrs 6 hrs 8 hrs 20 hrs Dissolution test 1 1021 30 51 66 97 using a small amount of dissolution medium Paddle method3 11 21 31 49 64 97

Table 2 shows that, under conditions wherein only a small amount of thedissolution medium is used, the active ingredient of the oralsustained-release preparation of the present invention exhibits asustained-release ability which is about the same as that exhibitedunder conditions wherein a large amount (900 ml) of the dissolutionmedium is present.

This means that a satisfactory amount of the active ingredient isreleased from the oral sustained-release preparation of the presentinvention even in the lower portion of the digestive tract (in which theamount of the internal liquid of the digestive tract is small).Therefore, the results of the above experiment suggest that the oralsustained-release preparation of the present invention is advantageous.

Experiment 3

A minicapsule for rats (diameter: about 2 mm, length: about 8 mm) wasfilled with the sustained-released coated particles produced in Example2 to thereby obtain a sustained-release capsule preparation for rats,wherein the sustained-release coated particles were used in an amountcorresponding to approximately 1.5 mg of fasudil hydrochlorideanhydride.

The obtained capsule preparation and 0.5 ml of water were orallyadministered to rats which had previously been fasted. At predeterminedpoints in time after the administration, blood samples were respectivelytaken from the rat and the concentration of the 1-hydroxy derivative offasudil hydrochloride (hereinafter referred to simply as the “activemetabolite”) in each blood sample was measured by the above-mentionedHPLC method.

FIG. 1 shows the change (with the lapse of time) of the concentration ofthe active metabolite in the blood taken from the rat.

It is apparent from FIG. 1 that, when the oral sustained-releasepreparation produced in Example 2 was orally administered, theconcentration of the active metabolite in the blood was maintained in adesired range for a long period of time.

Experiment 4

Substantially the same procedure as in Experiment 3 was repeated, exceptthat the sustained-release coated particles produced in Example 3 wereused instead of the sustained-release coated particles produced inExample 2.

FIG. 2 shows the change (with the lapse of time) of the concentration ofthe active metabolite in the blood taken from the rat.

It is apparent from FIG. 2 that, when the oral sustained-releasepreparation produced in Example 3 was orally administered, theconcentration of the active metabolite in the blood was maintained in adesired range for a long period of time.

Experiment 5

Substantially the same procedure as in Experiment 3 was repeated, exceptthat the sustained-release coated particles produced in Example 4 wereused instead of the sustained-release coated particles produced inExample 2.

FIG. 3 shows the change (with the lapse of time) of the concentration ofthe active metabolite in the blood taken from the rat.

It is apparent from FIG. 3 that, when the oral sustained-releasepreparation produced in Example 4 was orally administered, theconcentration of the active metabolite in the blood was maintained in adesired range for a long period of time.

Experiment 6

Substantially the same procedure as in Experiment 3 was repeated, exceptthat the sustained-release coated particles produced in Example 8 wereused instead of the sustained-release coated particles produced inExample 2.

FIG. 4 shows the change (with the lapse of time) of the concentration ofthe active metabolite in the blood taken from the rat.

It is apparent from FIG. 4 that, when the oral sustained-releasepreparation produced in Example 8 was orally administered, theconcentration of the active metabolite in the blood was maintained in adesired range for a long period of time.

Experiment 7

Substantially the same procedure as in Experiment 3 was repeated, exceptthat the sustained-release coated particles produced in Example 10 wereused instead of the sustained-release coated particles produced inExample 2.

FIG. 5 shows the change (with the lapse of time) of the concentration ofthe active metabolite in the blood taken from the rat.

It is apparent from FIG. 5 that, when the oral sustained-releasepreparation produced in Example 10 was orally administered, theconcentration of the active metabolite in-the blood was maintained in adesired range for a long period of time.

Experiment 8

Substantially the same procedure as in Experiment 3 was repeated, exceptthat the coated particles produced in Comparative Example 3 were usedinstead of the sustained-release coated particles produced in Example 2.

FIG. 6 shows the change (with the lapse of time) of the concentration ofthe active metabolite in the blood taken from the rat.

It is apparent from FIG. 6 that, when the oral sustained-releasepreparation produced in Comparative Example 3 was orally administered,the concentration of the active metabolite in the blood rapidly,markedly increased and then rapidly, markedly decreased, so that it wasimpossible to maintain the concentration of the active metabolite in theblood in a desired range for a long period of time.

Experiment 9

Substantially the same procedure as in Experiment 3 was repeated, exceptthat the coated particles produced in Comparative Example 4 were usedinstead of the sustained-release coated particles produced in Example 2.

FIG. 7 shows the change (with the lapse of time) of the concentration ofthe active metabolite in the blood taken from the rat.

It is apparent from FIG. 7 that, when the oral preparation produced inComparative Example 4 was orally administered, the concentration of theactive metabolite in the blood did not satisfactorily increase, so thatit was impossible to maintain the concentration of the active metabolitein the blood in a desired range for a long period of time.

The results of Experiments 3 to 7 clearly show that, when the oralsustained-release preparation of the present invention was orallyadministered to rats, the concentration of the active metabolite in theblood was maintained in a desired range for a long period of time. Thereason for this is considered to be as follows. When the oralsustained-release preparation of the present invention was orallyadministered, a desired amount of the active ingredient was continued tobe released from the preparation over a long period of time, so that thereleased active ingredient was absorbed over the whole region of thedigestive tract of the rat and metabolized to the active metabolite,and, in turn, the active metabolite was continued to be transferred tothe circulating blood of the rat.

By contrast, with respect to the preparation of Comparative Example 3(used in Experiment 8), the reason for the unsatisfactory results ofExperiment 8 is considered to be as follows. When the oral preparationproduced in Comparative Example 3 was orally administered, the activeingredient was rapidly released from the preparation, so that theconcentration of the active metabolite in the blood rapidly increased.However, the release of the active ingredient was completed in a shortperiod of time. Accordingly, the concentration of the active metabolitein the blood rapidly decreased, so that it was impossible to maintainthe concentration in the blood in a desired range for a long period oftime.

Further, with respect to the preparation of Comparative Example 4 (usedin Experiment 9), the reason for the unsatisfactory results ofExperiment 9 is considered to be as follows. When the oral preparationproduced in Comparative Example 4 was orally administered, the activeingredient was released from the preparation at an extremely slow rate,so that the amount of the active ingredient released from thepreparation was unsatisfactory and, hence, the amount of the activeingredient absorbed by the digestive tract was unsatisfactory. As aresult, the concentration of the active metabolite in the blood did notsatisfactorily increase.

From the above, it is apparent that, for maintaining the concentrationof the fasudil hydrochloride-derived active metabolite-in the blood in adesired range for a long period of time, it is necessary that fasudilhydrochloride or a hydrate thereof be administered in the form of apreparation which exhibits the above-described desired dissolution rateswith respect to the active ingredient, as measured by theabove-described methods.

INDUSTRIAL APPLICABILITY

By using the oral sustained-release preparation of the presentinvention, it is possible to surely control the release of fasudilhydrochloride from the preparation, so that a desired amount of fasudilhydrochloride is continued to be released from the preparation for along period of time, and that the effect of fasudil hydrochloride ismaintained for a long period of time. Therefore, the frequency of theadministration of the preparation becomes low, so that the burden of thepatient who has to take the preparation can be decreased and thecompliance with respect to the administration of the preparation can beimproved. As a result, the therapeutic effect of fasudil hydrochlorideis rendered reliable. Therefore, the oral sustained-release preparationof the present invention is extremely useful.

1. An oral sustained-release preparation of fasudil, wherein thepreparation is sufficient when administered once to maintain aconcentration in the blood of an active metabolite of fasudil in adesired range for a period of time between about two hours and at leastabout twelve hours after administering the preparation.
 2. The oralsustained-release preparation of claim 1, wherein the concentration inthe blood of the active metabolite is at least about 20 ng/ml.
 3. Theoral sustained-release preparation of claim 1, wherein the preparationcomprises a coated particle comprising fasudil.
 4. The oralsustained-release preparation of claim 3, wherein the coated particlecomprises a core having a surface and a coating formed on the surface,wherein the core comprises the fasudil.
 5. The oral sustained-releasepreparation of claim 4, wherein the amount of fasudil in the core_is atleast about 30% by weight of the fasudil in_the preparation.
 6. The oralsustained-release preparation of claim 5, wherein the coating comprisesa coating base material and an insoluble auxiliary material.
 7. The oralsustained-release preparation of claim 6, wherein the coating basematerial comprises a pharmaceutically acceptable hydrophobic polymer ora hydrophilic polymer capable of forming a coating.
 8. The oralsustained-release preparation of claim 7, wherein the hydrophobicpolymer is selected from the group consisting of ethylcellulose,cellulose acetate and a copolymer of ethyl acrylate/methylmethacrylate/trimethylammonioethyl methacrylate chloride.
 9. The oralsustained-release preparation of claim 6, wherein the insolubleauxiliary material is selected from the group consisting of magnesiumstearate, calcium stearate, talc, titanium oxide and light anhydroussilicic acid.
 10. An oral sustained-release preparation for providing avasodilative activity to a mammal in need thereof, wherein thepreparation comprises a coated particle comprising fasudil, and whereinthe preparation provides a reliable therapeutic effect by providing afrequency of administration of not more than twice a day and maintaininga concentration in the blood of active metabolite in a desired range fora period of between about 2 hours and at least about twelve hours afteradministration.
 11. The oral sustained-release preparation of claim 10,wherein the coated particle comprises a core having a surface and acoating formed on the surface, wherein the core comprises the fasudil.12. The oral sustained-release preparation of claim 11, wherein thefasudil present in the core is_at least about 30% by weight of thefasudil in_the preparation.
 13. The oral sustained-release preparationof claim 12, wherein the coating comprises a coating base material andan insoluble auxiliary material.
 14. The oral sustained-releasepreparation of claim 13, wherein the coating base material comprises apharmaceutically acceptable hydrophobic polymer or a hydrophilic polymercapable of forming a coating.
 15. The oral sustained-release preparationof claim 14, wherein the hydrophobic polymer is selected from the groupconsisting of ethylcellulose, cellulose acetate and a copolymer of ethylacrylate/methyl methacrylate/trimethylammonioethyl methacrylatechloride.
 16. The oral sustained-release preparation of claim 13,wherein the insoluble auxiliary material is selected from the groupconsisting of magnesium stearate, calcium stearate, talc, titanium oxideand light anhydrous silicic acid.
 17. An oral sustained-releasepreparation of fasudil, wherein the preparation is sufficient whenadministered once to maintain a desired concentration of activemetabolite in the blood for a period of between about two hours and atleast about twelve hours after administration, wherein the desiredconcentration is at least about one third of a maximal concentration ofactive metabolite reached in the blood during said period.
 18. An oralsustained-release preparation comprising fasudil, wherein thepreparation exhibits a dissolution rate of fasudil into 900 ml ofdistilled water at 37±0.50° C. with a paddle revolution rate of 100±4rpm of about 5 to 40% by weight after 3 hours, and when administeredonce to a mammal, the preparation provides a concentration of an activemetabolite of fasudil in the blood within a desired range for a periodof between about two hours and at least about twelve hours afteradministration.
 19. A method for treating a mammal having an ischemiccondition, comprising administering the oral sustained-releasepreparation according to claim
 1. 20. A method for maintaining aconcentration in the blood of an active metabolite of fasudil of atleast about 20 ng/ml for a period of between about 2 hours and at leastabout twelve hours after administering a single dose of the fasudil,comprising administering said dose in the form of an oralsustained-release preparation comprising a coated particle comprisingthe fasudil.